This invention relates to a group of novel vasopressin analogs and methods of treatment using these compounds to increase the level of Factor VIII and Plasminogen activator in the blood.
Plasminogen activator (PA) is one of the substances in the fibrinolytic system which leads to the conversion of plasminogen to plasmin, the enzyme which lyses fibrin and thereby limits blood clotting. Factor VIII (F-VIII) is a blood factor which aids in the clotting of blood by causing prothrombin to be converted to thrombin, which in turn causes fibrinogen to be converted to fibrin. Some mammals including humans do not have any F-VIII or do not have sufficient amounts of F-VIII to clot their blood in a normal time period. This is due to a hereditary disease called hemophilia and is marked by a tendency towards bleeding and hemorrhaging. Many varieties of this disease exist but all involve defects of the clotting mechanism of the blood. A related blood clotting disease is von Willebrand's disease in which bleeding time is prolonged and the patient has a low level of anti-hemophilia globulins (AHG).
It has been known since 1961 (Schneck, A. S. von Kaulla, K. N., Neurology ii:959; Cho, M. H. and Choy. W., Thrombosis et Diathesis Haemorrhagica 11:372, 1964) that two pressor, vasoconstrictor hormones, adrenaline and vasopressin, can increase the blood levels of both PA and F-VIII in mammals (Cash, J. D., Gader, A. M. A., Mulder, J. L. and Cort, J. H., Clin.Sci.Molec.Med. 54:403, 1978 and Prowse, C. V., Sas. G., Gader A. M. A., Cort. J. H. and Cash, J. D. Brit. J. Haematol. 41:437, 1979). The initial mechanism of action for this effect was considered to be a mechanical "squeezing" on the vascular endothelial cells considered to be the source of the F-VIII and PA. This theory was proven to be invalid when later studies (Cf. references above) showed that other pressor substances such as angiotensin II and oxytocin had no effect on increasing F-VIII and
in blood and vasopressin-related peptides such as arginine-vasotocin, in equipressor doses, were far less active. In addition, non-pressor analogs of vasopressin such 1-desamino-[8-D-ARG]-vasopressin (dDAVP-desmopressin) and 1-desamino-6-monocarba-[8 -D-Arg]-vasopressin (dCDAVP) both had highly potent and prolonged effects on F-VIII and PA release.
Compounds such as desmopressin have been used in the treatment of hemophilia A and B and von Willebrand's disease. It increases low levels of F-VIII toward normal and allows surgery without administration of exogenous F-VIII plasma fractions (anti-hemophilia globulins=AHG) (Mannucci, P. M., Ruggeri, Z. M., Pareti, F. I. and Capitanio, A., Lancet i:869, 1977). The clinical use of desmopressin, however, is complicated by the pronounced and long-acting antidiuretic action of the analog which has resulted in undesired water retention by the patients (Lowe, G., Pettigrew, A., Middleton, S., Forces C. D., Prentice, C. R. M., Lancet ii:614 (1977).